Hydroxyalkanoyl aminopyrazoles and related compounds

Abstract

This invention is directed to a class of compounds (Formula I) including hydroxyalkanoyl amino pyrazoles, hydroxyalkanoyl amino thiadiazoles, hydroxyalkanoyl amino acid esters, hydroxyalkanoyl amino acid amides, hydroxyalkanoyl amino alcohols, hydroxyalkanoyl amino ketoes, hydroxyalkanoyl amino hydantoins, hydroxyalkanoyl anilines, and hydroxyalkanoyl derivatives of privileged structures. The invention is also directed to a pharmaceutical formation comprising such compound in a pharmaceutically acceptable salt form or prodrug thereof. The invention is further directed to a method for inhibiting β-amyloid peptide release and/or synthesis, a method for inhibiting γ-secretase activity and a method for treating neurological disorders associated with β-amyloid peptide production. The method comprises administering to a host a pharmaceutical formulation comprising an effective amount of a compound of Formula I. The compounds of Formula I are useful in the prevention and treatment of Alzheimer's disease.

1. A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form or thereof,
 wherein X is 
 
       
         
           
           
               
               
           
         
         Q is Q 1 ,
 (C 1 –C 3  alkyl)-O-Q 1 , 
 (C 1 –C 3  alkyl)-S-Q 1 , 
 (C 1 –C 3  alkyl)-S(═O)-Q 1 , 
 (C 1 –C 3  alkyl)-S(═O) 2 -Q 1 , or 
 (C 1 –C 3  alkyd)-N (R 20 )-Q 1 ; 
 
         Q 1  is C 1 –C 6  alkyl;
 (C 2 –C 6  alkenyl substituted with 0–3 R 1a ; 
 (C 2 –C 6  alkynyl substituted with 0–3 R 1a ; 
 C 3 –C 10  cycloalkyl substituted with 0–3 R 1b ; 
 C 3 –C 10  carbocycle substituted with 0–3 R 1b ; or 
 C 6 –C 10  aryl substituted with 0–3 R 1b ; 
 
         R 10  is C 1 –C 6  alkyl substituted with 0–3 R 1a ;
 (C 2 –C 6  alkenyl substituted with 0–3 R 1a ; 
 (C 2 –C 6  alkynyl substituted with 0–3 R 1a ; 
 C 3 –C 10  cycloalkyl substituted with 0–3 R 1b ; 
 C 3 –C 10  carbocycle substituted with 0–3 R 1b ; or 
 C 6 –C 10  aryl substituted with 0–3 R 1b ; 
 
         R 1a , at each occurrence, is independently selected from the group consisting of:
 H, C 1 –C 6  alkyl, OR 14 , Cl, F, Br, I, NR 15 R 16 , CF 3 ; 
 C 3 –C 10  carbocycle substituted with 0–3 R 1b ; and 
 C 6 –C 10  aryl substituted with 0–3 R 1b ; 
 
         R 1b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 –C 6  alkyl, C 1 –C 4  alkoxy, C 1 –C 4  haloalkyl, C 1 –C 4  haloalkoxy, C 1 –C 4  haloalkyl-S—, and (C 1 –C 6  alkyl)-O—C (═O)—; 
         R 2  is H, methyl, ethyl, propyl, or butyl; 
         R 3  is H, C 1 –C 4  alkyl, —C(═O)(C 1 –C 4  alkyl), or —C(═S)(C 1 –C 4  alkyl); 
         R 5  is H, OR 14 ;
 C 1 –C 6  alkyl substituted with 0–3 R 5b ; 
 C 1 –C 6  alkoxy substituted with 0–3 R 5b ; 
 (C 2 –C 6  alkenyl substituted with 0–3 R 5b ; 
 (C 2 –C 6  alkynyl substituted with 0–3 R 5b ; 
 C 3 –C 10  cycloalkyl substituted with 0–3 R 5c ; 
 C 3 –C 10  carbocycle substituted with 0–3 R 5c ; or 
 C 6 –C 10  aryl substituted with 0–3 R 5c ; 
 
         R 5a  is H, C 1 –C 4  alkyl, or C 2 –C 4  alkenyl; 
         R 5b  at each occurrence, is independently selected from the group consisting of:
 H, C 1 –C 6  alkyl, CF 3 , OR 14 , Cl, F, Br, I, ═O, CN, NO 2 , NR 15 R 16 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , (C 2 –C 6  alkenyl, (C 2 –C 6  alkynyl, C 1 –C 4  alkoxy, C 1 –C 4  haloalkyl, C 1 –C 4  haloalkoxy, and C 1 –C 4  haloalkyl-S—, 
 C 3 –C 10  cycloalkyl substituted with 0–3 R 5c ; 
 C 3 –C 10  carbocycle substituted with 0–3 R 5c ; and 
 C 6 –C 10  aryl substituted with 0–3 R 5c ; 
 
         R 5c , at each occurrence, is independently selected from the group consisting of H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O)CH 3 , C 1 –C 6  alkyl, C 1 –C 4  alkoxy, C 1 –C 4  haloalkyl, C 1 –C 4  haloalkoxy, and C 1 –C 4  haloalkyl-S—; 
         R 14 , at each occurrence, is independently selected from the group consisting of H, phenyl, benzyl, C 1 –C 6  alkyl, and (C 2 –C 6  alkoxyalkyl; 
         R 15 , at each occurrence, is independently selected from the group consisting of H, C 1 –C 6  alkyl, phenyl, benzyl, phenethyl, (C 1 –C 6  alkyl)-C(═O)—, (C 1 –C 6  alkyl)—O—C(═O)— and (C 1 –C 6  alkyl)-S(═O) 2 —; and 
         R 16 , at each occurrence, is independently selected from the group consisting of H, C 1 –C 6  alkyl, phenyl, benzyl, phenethyl, (C 1 –C 6  alkyl)—C(═O)—, (C 1 –C 6  alkyl)—O—C(═O)— and (C 1 –C 6  alkyl)-S(═O) 2 —. 
       
     
     
       2. The compound according to  claim 1 , wherein
 R 10  is —C(CH 3 ) 2  phenyl. 
 
     
     
       3. The compound according to  claim 1  or  2 , wherein
 Q is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2CH   3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 ,
 —CH═CH 2 , —CH 2 CH═CH 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═C(CH 3 ) 2 , —CH 2 CH 2 CH═CH 2 , —CH 2 CH 2 C(CH 3 )═CH 2 , cis-CH 2 CH═CH(CH 3 ), cis-CH 2 CH 2 CH═CH(CH 3 ); trans-CH 2 CH═CH(CH 3 ), trans CH 2 CH 2 CH═CH(CH 3 ), —C≡CH, —CH 2 C≡CH, —CH 2 C≡C(CH 3 ), 
 cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4 propoxyphenyl-, 
 
 R 2  is H or methyl; 
 R 5  is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 H 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 ,
 —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CF 3 , 
 —CH═CH 2 , —CH 2 CH═CH 2 , —CH 2 CH 2 CH═CH═CH 2 , —CH═CHCH 3 , cis-CH 2 CH═CH (CH 3 ), trans-CH 2 CH═CH(CH 3 ), trans-CH 2 CH═CH(C 6 H 5 ), —CH 2 CH═C(CH 3 ) 2 , cis-CH 2 CH═CHCH 2 CH 3 , trans-CH 2 CH═CHCH 2 CH 3 , cis-CH 2 CH 2 CH═CH(CH 3 ), trans-CH 2 CH 2 CH═CH(CH 3 ), trans-CH 2 CH═CHCH 2 (C 6 H 5 ), 
 —C═CH, —CH 2 C═CH, —CH 2 C═C(CH 3 ), —CH 2 C═C(C 6 H 5 ), —CH 2 CH 2 C═CH, —CH 2 CH 2 C═C(CH 3 ), —CH 2 CH 2 C═C(C 6 H 5 ), —CH 2 CH 2 CH 2 C═CH, —CH 2 CH 2 CH 2 C═C(CH 3 ), —CH 2 CH 2 CH 2 C═C(C 6 H 5 ), 
 cyclopropyl-CH 2 —, cyclobutyl-CH 2 —, cyclopentyl-CH 2 —, cyclohexyl-CH 2 —, (2-CH 3 -cyclopropyl)CH 2 —, (3-CH 3 -cyclobutyl)CH 2 —, cyclopropyl-CH 2 CH 2 —, cyclobutyl-CH 2 CH 2 —, cyclopentyl-CH 2 CH 2 —, cyclohexyl-CH 2 CH 2 —, (2-CH 3 -cyclopropyl)CH 2 CH 2 —, (3-CH 3 -cyclobutyl)CH 2 CH 2 —, 
 phenyl-CH 2 —, (2-F-phenyl)CH 2 —, (3-F-phenyl)CH 2 —, (4-F-phenyl)CH 2 —, (3,5-diF-phenyl)CH 2 —, 
 phenyl-CH 2 CH 2 —, (2-F-Phenyl)CH 2 CH 2 —, (3-F-phenyl)CH 2 CH 2 —, (4-F-phenyl)CH 2 CH 2 —, 
 methoxy, ethoxy, propoxy, or butoxy; and 
 
 R 5a  is H. 
 
     
     
       4. The compound according to  claim 1 , wherein R 5  is C 3 –C 10  carbocycle substituted with 0–3 R 5c . 
     
     
       5. The compound according to  claim 1 , wherein Q is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ). 
     
     
       6. The compound according to  claim 1 , wherein R 10  is C 1 –C 6  alkyl substituted with 0–3 R 1a . 
     
     
       7. The compound according to  claim 1 , wherein
 R 10  is —C(CH 3 ) 2  phenyl; 
 R 5  is C 3 –C 10  carbocycle; 
 R 5a  is H; 
 Q=Q 1 =methyl; 
 R 2 =H; and 
 OR 3 =OH.